Chemically, adapalene is 6-[3-(1-adamantyl)-4-methoxyphenyl] naphthalene-2-carboxylic and belongs to the chemical group known as retinoids. Retinoids are chemical compounds structurally related to vitamin A. Their influence over epithelial cell growth has been exploited in a variety of medical contexts, especially in the area of treating skin conditions, particularly acne. Retinoids include first generation compounds such as retinol, tretinoin and isotretinoin; second generation compounds such as etretinate and acitretin; and third generation compounds such as tazarotene and adapalene. All retinoids are amphipathic, containing a cyclic end group, a polyene side chain and a polar end group.
While useful for treatment of skin conditions, adapalene can also cause undesirable side effects, especially with prolonged high exposure. Much of such toxicity is associated with blood uptake and resulting non-local effects that occur outside the area of topical administration.
Due to their chemical structure, retinoids have a very low water solubility. Particularly, the solubility of adapalene is 4×10−6 mg/mL. This characteristic makes their incorporation into topical pharmaceutical preparations extremely challenging. In the current state of the art, two different approaches have been used to address this challenge: the first one is the dispersion of adapalene in finely divided or micronized particles, within a pharmaceutically acceptable base such as cream, gel, lotion, or ointment; the second one is the solubilización of adapalene in bases formed by non-aqueous excipients.
Whatever the approach used in the current state of the art, it has limitations which do not allow the maximum benefit that the topical use of adapalene can provide. First, according to the essential principles governing the penetration of substances through the skin, the initial step of the transport process consists in the dissolution of the molecules in a vehicle. Next, molecules partition into lipids of the stratum corneum, this means that the molecules pass from the hydrophilic environment composed of the vehicle to the lipophilic environment composed of the lipids that make up the outer layer of the stratum corneum. The molecules of active ingredients must then diffuse through the stratum corneum and reach the epidermis where inverse partition into the hydrophilic environment takes place. Inverse partition means that the molecules go from the lipophilic environment in which they were dissolved within the stratum corneum, to the hydrophilic environment of the viable epidermis.
When adapalene is dispersed as fine particles in an aqueous vehicle, its penetration is highly limited to the fraction that could be dissolved at the interface formed by the vehicle and stratum corneum of the skin, thereby limiting the amount and speed with which the active pharmaceutical ingredient penetrates and becomes available in the epidermis, where it should exert its pharmacological action.
On the contrary, if the approach to be used is to dissolve the adapalene in vehicles formed by non-aqueous solvents, the limitation is the fat or oily sensation created by this type of vehicles when the product is applied to the skin, leading to poor product acceptance by the patient, especially when considering that acne is the condition where adapalene is more often used. U.S. Pat. No. 7,579,377, U.S. Pat. No. 7,737,181, U.S. Pat. No. 7,834,060, U.S. Pat. No. 7,838,558, U.S. Pat. No. 7,868,044, U.S. Pat. No. 8,653,140, U.S. Pat. No. 8,703,820, U.S. Pat. No. 8,729,127, and U.S. Pat. No. 8,921,423 describe pharmaceutical compositions containing adapalene at a concentration of 0.3% by weight, which is suspended, undissolved, in a gel, cream, or lotion vehicle.
U.S. Pat. No. 8,716,341 describes pharmaceutical compositions containing adapalene from 0.02% to 0.04% by weight, which is suspended, undissolved, in a gel, cream, or lotion vehicle.
U.S. patent application US20090318371 (the “e'371 application”) describes a combination of adapalene or tazarotene with clindamycin phosphate and benzoyl peroxide. This application does not specify whether adapalene is dissolved or suspended into the vehicle; however, from the described formulation, it is easily deductible that adapalene is not dissolved, since the solvent and quantities used for this purpose are not enough to get a true solution. The selected solvent is ethyl alcohol in a percentage of up to 10% of the total composition. In the best-case scenario covered by this application, adapalene 50 mg should be dissolved in a maximum of 10 g, equivalent to 12.7 mL, of ethyl alcohol. The concentration of adapalene in that composition is 50 mg/12.7 mL or 3.94 mg/mL. The solubility of adapalene in ethyl alcohol is 1 mg/mL. Thus, the mixture in the '371 application, with a concentration of 3.94 mg/mL, would not result in full dilution of adapalene.
U.S. Pat. No. 7,998,467 describes pharmaceutical compositions containing topical adapalene dispersed in polyurethane polymers in order to improve its absorption. As in the aforementioned documents, adapalene is not soluble in the preparation.
U.S. Pat. No. 8,404,220 describes a manufacturing process, at industrial scale, of adapalene aqueous gels, in which the active pharmaceutical ingredient is dispersed, undissolved, within a gel.
Japanese patent applications JP2008273941, JP2008255017, and JP2008184446, like the Chinese patent CN103462882, and patent application CN1989956 describe pharmaceutical preparations of adapalene, alone or in combination with other active pharmaceutical ingredients, in which it is explicitly stated that adapalene is suspended, undissolved, in the vehicle.
U.S. Pat. No. 5,212,303 describes both pharmaceutical preparations where adapalene is suspended, undissolved, in aqueous vehicles, and pharmaceutical preparations where adapalene is dissolved in a non-aqueous mixture of polyethylene glycol 400 and ethyl alcohol in a ratio of 70:30. The vehicle without water, which also has a 70% of polyethylene glycol, creates an oily sensation causing rejection by the patient, especially when considering that acne is the condition where adapalene is more often used.